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Clinical implication of reversing epigenetic modification of tumor suppressor genes

Clinical implication of reversing epigenetic modification of tumor suppressor genesClinical implication of reversing epigenetic modification of tumor suppressor genes

 

Unlike mutagenic events, epigenetic events in cancer can also be reversed to restore the function of key control pathways in malignant and pre-malignant cells. For that reason, one of my major goals is to define the efficiency of epigenetic drags (such as DNA methylation inhibitors, HDACs inibitors, etc.)  for the treatment of acute promyelocytic leukemia (APL) as well as other acute myeloid leukemias. 

Preliminary results in this direction are highly promising. Blood cells isolated from AML-patients can be re-routed to the “normal differentiation program” if treated with combination of HDAC inhibitor and demethylating agent (such as 5- Aza-dC), or with retinoic acid (the natural ligand of RAR) and demethylating agent (Figure X).

On a parallel line of investigation, we are exploring the possibility of applying knock-down technology as a tool for therapeutic intervention (see Cancer Cell, 11, 513-525).

Selected publications from our group on this research line:

  • Villa R, Pasini D, Gutierrez A, Viré E, Nomdedeu JF, Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, and Di Croce L (2007) Role of the Polycomb repressive complex 2 in leukemia. Cancer Cell, 11, 513-525.
  • Fazi F., Zardo G., Gelmetti V., Travaglini L., Ciolfi A., Di Croce L., Rosa A., Bozzoni I., Grignani F., Lo-Coco F., Pelicci PG., and Nervi C.  (2007) Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood, 109, 4432-4440.
  • Di Croce, L., (2005) Chromatin modifying activity of leukemia associated fusion proteins. Hum Mol Genet 14, R77-R84.
  • Di Croce, L., Raker V.A., Corsaro M., Fazi, F., Fanelli M., Fuks, F., Lo Coco, F., Kouzarides, T., Nervi, C., Minucci, S. and Pelicci, P.G. (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082.

Fig. 1. (A) WrightGiemsa staining of blood cells isolated from a newly diagnosed AML patient either untreated (i) or treated for 48 hours with RA (ii) or 5-Aza-dC (iii) or a combination of these (iv). The inserts show representative undifferentiated le (B) Morphologic differentiation of SUZ12 knockdown NB4 and HL60 cells. Leukemic cells were stained with Wright-Giemsa and analyzed for the morphology under the light microscopy